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NEDD8-activating enzyme inhibition induces cell cycle arrest and anaphase catastrophe in malignant T-cells

Authors
  • Kittai, Adam S.
  • Danilova, Olga V.
  • Lam, Vi
  • Liu, Tingting
  • Bruss, Nur
  • Best, Scott
  • Fan, Guang
  • Danilov, Alexey V.
Type
Published Article
Journal
Oncotarget
Publisher
"Impact Journals, LLC "
Publication Date
Sep 28, 2021
Volume
12
Issue
20
Pages
2068–2074
Identifiers
DOI: 10.18632/oncotarget.28063
PMID: 34611480
PMCID: PMC8487718
Source
PubMed Central
Keywords
Disciplines
  • Research Paper
License
Unknown

Abstract

Peripheral T-cell lymphoma (PTCL) is characterized by poor outcomes. We and others have shown that targeting the NEDD8-activating enzyme (NAE) with an investigational inhibitor pevonedistat deregulates cell cycle and mitosis in lymphoma and leukemia. Here, we report that PTCL is characterized by increased rate of chromosomal instability. NAE inhibition promotes cell cycle arrest and induces multipolar anaphases in T-cell lymphoma cell lines, resulting in apoptosis, also observed in primary malignant PTCL cells treated with pevonedistat. We identified p27Kip1 as a mediator of anaphase catastrophe in these cells. Targeting neddylation with pevonedistat may be a promising approach to treatment of PTCL.

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